Recent studies from our laboratory have demonstrated that tissue insensitivity to insulin is the primary cause of glucose intolerance in uremia. The observed insulin resistance could result from: (a) decreased glucose metabolism by peripheral tissues, (b) decreased glucose uptake by the liver, or (c) increased basal hepatic glucose production which is not normally suppressed by insulin. In the present proposal we plan to examine each of these possibilities employing the insulin clamp technique in combination with hepatic and femoral venous catheterization, tritiated glucose, and/or indirect calorimetry. We will also define the relative contributions of receptor versus postreceptor defects to the insulin resistance by: (1) examining the in vivo dose response curve relating insulin binding to insulin action and (2) examining insulin-mediated glucose metabolism in uremic and control subjects at comparable levels of insulin binding, and (3) quantitating insulin binding, glucose transport and glucose metabolism in the soleus muscle of chronically uremic rats. The ability of physical training to improve the defect in insulin-mediated metabolism will be examined. It is well known that negative nitrogen balance and muscle wasting present significant problems in the management of the uremic patient. Therefore, we plan to study amino acid tolerance before and after dialysis by examining: (a) hepatic and leg exchange of amino acids following protein ingestion, (b) the effect of insulin (insulin clamp) and hyperglycemia (hyperglycemic clamp) on leg and liver amino acid exchange, (c) branched chain amino acid metabolism using 14C-leucine, and (d) 14C-alanine and 14C-glutamine turnover in combination with hepatic and femoral venous catheterization.